A University of Pennsylvania research team has published groundbreaking results in Nature Biomedical Engineering, achieving a dual breakthrough in mRNA vaccine efficacy and safety by improving a key component of the delivery vehicle—lipid nanoparticles (LNPs). Using the century-old Mannich reaction, the team synthesized a library of phenol-containing ionizable lipids, opening new pathways for mRNA technology in infectious disease prevention, cancer therapy, and beyond.

The team innovatively leveraged the Mannich reaction to construct novel ionizable lipids incorporating phenolic groups. Senior author Professor Michael J. Mitchell stated: "Phenol-containing lipids both alleviate inflammation at the injection site and enhance mRNA delivery efficiency." Experiments showed that the optimized C-a16 LNP increased fluorescent reporter gene expression by 15-fold while significantly reducing oxidative stress markers. This "anti-inflammatory + potency-boosting" property stems from the phenol group's ability to scavenge free radicals, thereby minimizing cellular damage and improving the microenvironment.

In applied testing, phenol-containing lipids demonstrated broad potential:

Gene Editing: More than 2× improvement in CRISPR-mediated gene correction efficiency

Cancer Therapy: 3× greater tumor suppression with an mRNA melanoma vaccine, along with enhanced T-cell activity

Infectious Disease Prevention: Immune response to a COVID-19 vaccine 5× stronger than standard formulations

Co-first author Dongyoon Kim noted: "C-a16 lipids maintain cellular homeostasis, allowing LNPs to perform their delivery mission more efficiently." The technology holds significant value not only for prophylactic vaccines but also for the development of therapeutic nucleic acid drugs.